Zetterberg Henrik, Regland Björn, Palmér Mona, Ricksten Anne, Palmqvist Lars, Rymo Lars, Arvanitis Demetrios A, Spandidos Demetrios A, Blennow Kaj
Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg University, Sweden.
Eur J Hum Genet. 2002 Feb;10(2):113-8. doi: 10.1038/sj.ejhg.5200767.
The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.
自然流产的发病机制复杂，可能涉及多种遗传和环境因素的相互作用。亚甲基四氢叶酸还原酶（MTHFR）基因C677T和A1298C多态性通常与叶酸依赖性同型半胱氨酸代谢缺陷相关，并被认为是早期妊娠反复胚胎丢失的危险因素。在本研究中，我们使用固相测序技术确定了自然流产胚胎（受孕后第六至二十周胎儿死亡）和成年对照的DNA样本中MTHFR C677T和A1298C联合多态性的患病率。与野生型联合基因型（677CC/1298AA）相比，自然流产胚胎中一个或多个677T和1298C等位基因的患病率的优势比为14.2（95%可信区间1.78-113），表明MTHFR多态性可能对胎儿存活有重大影响。任何组中均未检测到包含三个或四个突变等位基因的联合677CT/1298CC、677TT/1298AC或677TT/1298CC基因型，这表明两种多态性之间存在完全连锁不平衡。本研究发现自然流产胚胎中MTHFR突变基因型的高患病率强调了孕前补充叶酸的潜在保护作用。
